The present invention relates to a series of novel N-acryloylpiperazine derivatives which have PAF antagonist activity and provides processes for preparing these deriviatives, as well as methods and compositions using them for the treatment of various diseases and disorders arising from the imbalances in the PAF system in the mammalian, e.g. human, body.
The abbreviation "PAF" as used herein means, as is conventional "platelet activating factor".
Natural PAF, at least as isolated from mammalian tissues, is a mixture of from 2 to 5 phospholipids, the number depending upon the nature of the original tissue. The formulae of the major constituents of PAF are now well know. Natural PAF is levorotatory and the various components of natural PAF may be identified, for examples as: l-C.sub.16:0 =PAF where the alkoxy group at the PAF 1-position is a hexadecyloxy group; l-C.sub.18:0 =PAF where the alkoxy group at the PAF 1-position is an octadecyloxy group; or l-C.sub.18:1 =PAF where the alkoxy group at the PAF 1-position is a 9-(Z)-octadecenyloxy group. The convention used above for identifying the constituents of PAF gives the rotation first (l, in the above examples), followed by the number of carbon atoms in the 1-alkoxy group, and finally the number of double bonds.
PAF exhibits effect, from which it derives its name. It has, however, in recent years been seen to be a potentially crucial mediator in a wide variety of pathological processes. Thus, it also has a hypotensive effect and increases vasopermeability; it is believed to be an active agent in the induction of the shock state (for example endotoxin-induced shock or anaphylactic shock) and to act as a mediator of inflammatory disease. It has also been found to play an important role in nephritis, myocardial infarction, angina pectoris, asthma, cardiac and systemic anaphylaxis, gastric and intestinal ulceration, psoriasis and immune and renal disorders. In addition, it is believed that PAF antagonists may be useful for prophylaxis of rejection in organ transplantation.
It is not, therefore, surprising that, as a result, PAF antagonists have been investigated with a view to developing new types of treatment for the above pathologies, and notably new types of anti-shock agent and anti-inflammatory agent. Accordingly, various compounds have been investigated in an attempt to find such PAF antagonists, and, currently, several compounds are known as PAF antagonists. Although the chemical structure of known PAF antagonists varies widely, and there appears to be no obvious common factor linking all of their chemical structures, in general, known materials having PAF-antagonist activity may be classified according to their chemical structure as either PAF type or non-PAF type compounds. The compounds of the present invention are non-PAF type compounds, and specifically are compounds containing an N-acryloylpiperazine or N-acryloylhomopiperazine system.
Amongst known such compounds which have structures similar to those of the compounds of present invention and which are said to have similar types of activities are:
the pentadienylamido compounds disclosed, inter alia, in U.S. Pat. No. 4,788,206; PA1 the alkenyl-, alkenoyl- or thioalkenoyl- amido compounds disclosed, inter alia, in European Patent Publication No. 298 466; and PA1 the polycycloalkylcarbonyl- piperazine or homopiperazine compounds disclosed, inter alia, in European Patent Publication No. 284 359. PA1 R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a cyano group, or a group having the formula --R.sup.5 in which R.sup.5 is as defined above; PA1 X represents an oxygen atom or a sulfur atom; PA1 A represents a 1,4-piperazin-1,4-diyl group or a 1,4-homopiperazin-1,4-diyl group; PA1 B' represents a C.sub.1 -C.sub.6 alkylene group, a carbonyl group, a thiocarbonyl group, a sulfinyl group or a sulfonyl group; PA1 R.sup.4 represents an unsubstituted phenyl group or a substituted phenyl group having from 1 to 5 substituents selected from the group consisting of substituents (a) and substituents (b), defined below; PA1 C.sub.1 -C.sub.22 alkyl groups; C.sub.1 -C.sub.22 alkoxy groups; C.sub.1 -C.sub.6 haloalkyl groups; hydroxy groups; C.sub.1 -C.sub.4 alkylenedioxy groups; C.sub.1 -C.sub.22 aliphatic carboxylic acyloxy groups; substituted C.sub.1 -C.sub.6 aliphatic carboxylic acyloxy groups having at least one substituent selected from the group consisting of substituents (c), defined below; C.sub.7 -C.sub.15 carbocyclic aromatic carboxylic acyloxy groups; substituted C.sub.7 -C.sub.15 carbocyclic aromatic carboxylic acyloxy groups having at least one substituent selected from the group consisting of substituents (d), defined below; C.sub.8 -C.sub.15 aralkyloxycarbonyloxy groups in which the aryl part is unsubstituted or has at least one substituent selected from the group consisting of substituents (d) defined below; C.sub.1 -C.sub.6, alkanesulfonyloxy groups in which the alkane part is unsubstituted or has at least one substituent selected from the group consisting of substituents (c), defined below; arylsulfonyloxy groups in which the aryl part is unsubstituted or has at least one substituent selected from the group consisting of substituents (d), defined below; halogen atoms; and nitro groups; PA1 C.sub.1 -C.sub.6 alkylsulfonyl groups; C.sub.1 -C.sub.6 alkylsulfinyl groups; and C.sub.1 -C.sub.6 alkylthio groups; PA1 C.sub.1 -C.sub.6 alkyl groups; C.sub.1 -C.sub.6 haloalkyl groups; halogen atoms; C.sub.1 -C.sub.6 alkoxy groups; and (C.sub.1 -C.sub.6 alkanoyloxy)methoxycarbonyl groups; PA1 C.sub.1 -C.sub.6, alkyl groups; C.sub.1 -C.sub.6 alkoxy groups; halogen atoms; unsubstituted C.sub.6 -C.sub.10 aryl groups; nitro groups; and (C.sub.1 -C.sub.6 alkoxy)carbonyl groups; PA1 C.sub.1 -C.sub.22 alkyl groups, which may be straight or branched chain groups, such as the methyl, ethyl, propyl, isopropyl, buryl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, t-pentyl, isohexyl, 1-methylpentyl, heptyl, 1-methylhexyl, 2-methylhexyl, 5-methylhexyl, 3-ethylpentyl, octyl, 2-methylheptyl, 5-methylheptyl, 2-ethylhexyl, 2-ethyl-3-methylpentyl, 3-ethyl-2-methylpentyl, nonyl, 2-methyloctyl, 7-methyloctyl, 4-ethylheptyl, 3-ethyl-2-methylhexyl, 2-ethyl-1-methylhexyl, decyl, 2-methylnonyl, 8-methylnonyl, 5-ethyloctyl, 3-ethyl-2-methylheptyl, 3,3-diethylhexyl, undecyl, 2-methyldecyl, 9-methyldecyl, 4-ethylnonyl, 3, 5-dimethylnonyl, 3-propyloctyl, 5-ethyl-4-methyloctyl, dodecyl, 1-methylundecyl, 10-methylundecyl, 3-ethyldecyl, 5-propylnonyl, 3,5-diethyloctyl, tridecyl, 11-methyldodecyl, 7-ethylundecyl, 4-propyldecyl, 5-ethyl-3-methyldecyl, 3-pentyloctyl, tetradecyl, 12-methyltridecyl, 8-ethyldodecyl, 6-propylundecyl, 4-butyldecyl, 2-pentylnonyl, pentadecyl, 13-methyltetradecyl, 10-ethyltridecyl, 7-propyldodecyl, 5-ethyl-3-methyldodecyl, 4-pentyldecyl, hexadecyl, 14-methylpentadecyl, 6-ethyltetradecyl, 4-propyltridecyl, 2-butyldodecyl, heptadecyl, 15-methylhexadecyl, 7-ethylpentadecyl, 3-propyltetradecyl, 5-pentyldodecyl, octadecyl, 16-methylheptadecyl, 5-propylpentadecyl, nonadecyl, 17-methyloctadecyl, 4-ethylheptadecyl, icosyl, 18-methylnonadecyl, 3-ethyloctadecyl, henicosyl and docosyl groups, preferably a straight or branched chain alkyl group having from 1 to 6 carbon atoms, and more preferably a straight or branched chain alkyl group having from 1 to 4 carbon atoms; PA1 C.sub.1 -C.sub.22 alkoxy groups which nay be straight or branched chain groups, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, t-pentoxy, isohexyloxy, 1-methylpentoxy, heptyloxy, 1-methylhexyloxy, 2-methylhexyloxy, 5-methylhexyloxy, 3-ethylpentoxy, octyloxy, 2-methylheptyloxy, 5-methylheptyloxy, 2-ethylhexyloxy, 2-ethyl-3-methylpentoxy, 3-ethyl-2-methylpentoxy, nonyloxy, 2-methyloctyloxy, 7-methyloctyloxy, 4-ethylhexyloxy, 3-ethyl-2-methylhexyloxy, 2-ethyl- 1-methylhexyloxy, decyloxy, 2-methylnonyl oxy, 8-methylnonyloxy, 5-ethyloctyloxy, 3-ethyl-2-methylheptyloxy, 3,3-diethylhexyloxy, undecyloxy, 2-methyldecyloxy, 9-methyldecyloxy, 4-ethylnonyloxy, 3,5-dimethylnonyloxy, 3-propyloctyloxy, 5-ethyl-4-methyloctyloxy, dodecyloxy, 1-methylundecyloxy, 10-methylundecyloxy, 3-ethyldecyloxy, 5-propylnonyloxy, 3,5-diethyloctyloxy, tridecyloxy, 11-methyldodecyloxy, 7-ethylundecyloxy, 4-propyldecyloxy, 5-ethyl-3-methyldecyloxy, 3-pentyloctyloxy, tetradecyloxy, 12-methyltridecyloxy, 8-ethyldodecyloxy, 6-propylundecyloxy, 4-butyldecyloxy, 2-pentylnonyloxy, pentadecyloxy, 13-methyltetradecyloxy, 10-ethyltridecyloxy, 7-propyldodecyloxy, 5-ethyl-3-methyldodecyloxy, 4-pentyldecyloxy, hexadecyloxy, 14-methylpentadecyloxy, 6-ethyltetradecyloxy, 4-propyltridecyloxy, 2-butyldodecyloxy, heptadecyloxy, 15-methylhexadecyloxy, 7-ethylpentadecyloxy, 3-propyltetradecyloxy, 5-pentyldodecyloxy, octadecyloxy, 16-methylheptadecyloxy, 5-propylpentadecyloxy, nonadecyloxy, 17-methyloctadecyloxy, 4-ethylheptadecyloxy, icosyloxy, 18-methylnonadecyloxy, 3-ethyloctadecyloxy, henicosyl and docosyl groups, preferably a straight or branched chain alkoxy group having from 1 to 6 carbon atoms, and more preferably a straight or branched chain alkoxy group having from 1 to 4 carbon atoms; PA1 C.sub.1 -C.sub.6 haloalkyl groups, in which the alkyl part may be any one of those alkyl groups exemplified above, and is more preferably a C.sub.1 -C.sub.4 alkyl group, and the halogen atom may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom, such as the fluoromethyl, trifluoromethyl, difluoromethyl, dichloromethyl, dibromomethyl, trichloromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-haloethyl (e.g. 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl or 2-iodoethyl), 2,2-dibromoethyl, 2,2,2-tribromoethyl, pentafluoroethyl, 4-chlorobutyl, 4-bromobutyl and 4-fluorobutyl groups, preferably the trifluoromethyl, trichloromethyl and pentafluoroethyl groups; PA1 hydroxy groups; PA1 C.sub.1 -C.sub.4 alkylenedioxy groups in which the alkylene part may be a straight or branched chain group; examples include the methylenedioxy, dimethylenedioxy, trimethylenedioxy, tetramethylenedioxy, ethylidenedioxy and isopropylidenedioxy groups, of which the methylenedioxy group is preferred; PA1 unsubstituted C.sub.1 -C.sub.22 aliphatic carboxylic acyloxy groups, in which the acyl part may contain one or more carbon-carbon double or triple bonds or may be free from such bonds, and in the case of the unsaturated groups, the number of carbon atoms is preferably from 3 to 6; examples of such groups include the alkanoyloxy groups, such as the formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy, isovaleryloxy, octanoyloxy, nonylcarbonyloxy, decylcarbonyloxy, 3-methylnonylcarbonyloxy, 8-methylnonylcarbonyloxy, 3-ethyloctylcarbonyloxy, 3,7-dimethyloctylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy, tridecylcarbonyloxy, tetradecylcarbonyloxy, pentadecylcarbonyloxy, hexadecylcarbonyloxy, 1-methylpentadecyl carbonyl oxy, 14-methylpentadecylcarbonyloxy, 13,13-dimethyltetradecylcarbonyloxy, heptadecylcarbonyloxy, 15-methylhexadecylcarbonyloxy, octadecylcarbonyloxy, 1-methylheptadecyclcarbonyloxy, nonadecylcarbonyloxy, icosylcarbonyloxy, and henicosylcarbonyloxy groups; unsaturated analogs of these alkanoyloxy groups, especially the C.sub.3 -C.sub.6 alkenoyloxy and alkynoyloxy groups, such as the (E)-2-methyl-2-butenoyloxy group; alkoxycarbonyloxy groups, especially C.sub.2 -C.sub.7 alkoxycarbonyloxy groups (i.e. the alkoxy part is C.sub.1 -C.sub.6), such as the methoxycarbonyloxy, ethoxycarbonyloxy, t-butoxycarbonyloxy and isobutoxycarbonyloxy groups; such alkoxycarbonyloxy groups having one or more halogen or trialkylsilyl substituents (in which each alkyl group, which may be the same or different, has from 1 to 4 carbon atoms, and in which one such alkyl group may be replaced by a phenyl group), such as the 2,2,2-trichloroethoxycarbonyloxy and 2-trimethylsilylethoxycarbonyloxy groups; and the alkenyloxycarbonyloxy groups, such as the vinyloxycarbonyloxy and allyloxycarbonyloxy groups; PA1 substituted C.sub.1 -C.sub.6 aliphatic carboxylic acyloxy groups having at least one substituent selected from the group consisting of substituents (c), defined above and exemplified more generally below; the acyloxy part may be any of the C.sub.1 -C.sub.6 unsubstituted acyloxy groups exemplified above, and specific examples of the substituted groups include: the halogenated alkanoyloxy groups, such as the chloroacetoxy, dichloroacetoxy, trichloroacetoxy and triftuoroacetoxy groups; the alkoxyalkanoyloxy groups, such as the methoxyacetoxy group; and the (C.sub.1 -C.sub.6 alkanoyloxy)methoxycarbonyl groups, such as the pivaloyloxymethoxycarbonytoxy group; PA1 C.sub.7 -C.sub.15, preferably C.sub.7 -C.sub.11, carbocyclic aromatic carboxylic acyloxy groups (i.e. an arylcarbonyl group in which the aryl part is C.sub.6 -C.sub.14, preferably C.sub.6 -C.sub.10), which may be unsubstituted or may have one or more substituents selected from the group consisting of substituents (d), defined above and exemplified more generally below; examples of such unsubstituted groups include the benzoyloxy, .alpha.-naphthoyloxy and .beta.-naphthoyloxy groups; the substituted groups may be any of these unsubstituted groups but having at least one, and preferably from 1 to 5, more preferably from 1 to 3, substituents selected from the group consisting of substituents (d); examples of the substituted groups include: halogenated arylcarbonyloxy groups, such as the 2-bromobenzoyloxy and 4-chlorobenzoyloxy groups; arylcarbonyloxy groups substituted by one or more lower (i.e. C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4) alkyl groups, such as the 2,4,6-trimethylbenzoyloxy and p-toluoyloxy groups; arylcarbonyloxy groups substituted by one or more lower (i.e. C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4) alkoxy groups, such as the 4-anisoyloxy group; arylcarbonyloxy groups substituted by one or more nitro groups, such as the 4-nitrobenzoyloxy and 2-nitrobenzoyloxy groups; arylcarbonyloxy groups substituted by one or more lower (i.e. C.sub.2 -C.sub.7, preferably C.sub.2 -C.sub.5) alkoxycarbonyl groups, such as the 2-(methoxycarbonyl)benzoyloxy group; and arylcarbonyloxy groups substituted by one or more aryl groups, such as the 4-phenylbenzoyloxy group; PA1 C.sub.8 -C.sub.15 aralkyloxycarbonyloxy groups in which the aryl part is C.sub.6 -C.sub.10 and the alkyl part is correspondingly C.sub.1 -C.sub.4 ; these groups may be unsubstituted or may have at least one substituent, preferably on the aryl part or parts, selected from the group consisting of substituents (d), defined above and exemplified more generally below, preferably one or two lower alkoxy or nitro groups; the alkyl part is preferably unsubstituted; examples of such unsubstituted groups include the benzyloxycarbonyloxy group; and examples of such substituted groups include the unsubstituted groups referred to but having one or more, preferably from 1 to 5, more preferably from 1 to 3, of substituents (d), such as the 4-methoxybenzyloxycarbonyloxy, 3,4-dimethoxybenzyloxycarbonyloxy, 2-nitrobenzyloxycarbonyloxy and 4-nitrobenzyloxycarbonyloxy groups; PA1 C.sub.1 -C.sub.6 alkanesulfonyloxy groups in which the alkane part is unsubstituted or has at least one substituent selected from the group consisting of substituents (c), defined above and exemplified more generally below, preferably halogen atoms and more preferably fluorine atoms; examples of such groups include the lower (i.e. C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4) alkanesulfonyloxy groups, such as the methanesulfonyloxy, ethanesulfonyloxy and 1-propanesulfonyloxy groups; and fluorinated lower alkanesulfonyloxy groups, such as the trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy groups; PA1 arylsulfonyloxy groups in which the aryl part is C.sub.6 -C.sub.10 and may be unsubstituted or may have at least one substituent selected from the group consisting of substituents (d), defined above and exemplified more generally below; examples of such unsubstituted groups include the benzenesulfonyloxy group, and examples of such substituted groups include the unsubstituted groups referred to but having one or more, preferably from 1 to 5, more preferably from 1 to 3, of substituents (d), such as the p-toluenesulfonyloxy group; PA1 halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms, preferably the fluorine, chlorine and bromine atoms; and PA1 nitro groups. PA1 the C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4, alkyl groups, such as those exemplified above in relation to substituents (a); PA1 the C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4, haloalkyl groups, such as those exemplified above in relation to substituents (a), and especially the trifluoromethyl and pentafluoroethyl groups; PA1 halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms, especially the chlorine and fluorine atoms; PA1 the C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4, alkoxy groups such as those exemplified above in relation to substituents (a), and especially the methoxy group; and PA1 the (C.sub.1 -C.sub.6, alkanoyloxy)methoxycarbonyl groups such as the formyloxymethoxycarbonyl, acetoxymethoxycarbonyl, propionyioxymethoxycarbonyl, butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, valeryloxymethoxycarbonyl and isovaleryloxymethoxycarbonyl groups, especially the pivaloyloxymethoxycarbonyloxy group. PA1 the C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4, alkyl groups, such as those exemplified above in relation to substituents (a); PA1 the C.sub.1 -C.sub.6, preferably C.sub.1 -C.sub.4, alkoxy groups, such as those exemplified above in relation to substituents (a), and especially the methoxy group; PA1 halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms, especially the chlorine and fluorine atoms; PA1 C.sub.6 -C.sub.10 aryl groups which are not substituted, such as the phenyl or naphthyl groups; PA1 the nitro group; and PA1 C.sub.2 -C.sub.7 alkoxycarbonyl groups (i.e. the alkoxy part is C.sub.1 -C.sub.6), such as the methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl groups. PA1 lower alkylsulfonyl groups, which may have from 1 to 6, preferably from 1 to 4, carbon atoms in the alkyl part thereof, and which may be a straight or branched chain group such as those exemplified in relation to the alkyl group which may be included in substituents (a); examples of preferred such alkanesulfonyl groups include the methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, isobutanesulfonyl, sec-butanesulfonyl, t-butanesulfonyl, pentanesulfonyl, isopentanesulfonyl, 2-methylbutanesulfonyl, neopentanesulfonyl, hexanesulfonyl, 4-methylpentanesulfonyl, 3-methylpentanesulfonyl, 2-methylpentanesulfonyl, 3,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl, 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3-dimethylbutanesulfonyl and 2,3-dimethylbutanesulfonyl groups, of which the straight and branched chain alkanesulfonyl groups having from 1 to 4 carbon atoms are preferred; PA1 lower alkylsulfinyl groups, which may have from 1 to 6, preferably from 1 to 4, carbon atoms in the alkyl part thereof, and which may be a straight or branched chain group such as those exemplified in relation to the alkyl group which may be included in substituents (a); examples of preferred such alkanesulfinyl groups include the methanesulfinyl, ethanesulfinyl, propanesulfinyl, isopropanesulfinyl, butanesulfinyl, isobutanesulfinyl, sec-butanesulfinyl, t-butanesulfinyl, pentanesulfinyl, isopentanesulfinyl, 2-methytbutanesulfinyl, neopeneanesulfinyl, hexanesulfinyl, 4-methylpentanesulfinyl, 3-methylpentanesulfinyl, 2-methylpentanesulfinyl, 3,3-dimethylbutanesulfinyl, 2,2-dimethylbutanesulfinyl, 1,1-dimethylbutanesulfinyl, 1,2-dimethylbutanesulfinyl, 1,3-dimethylbutanesulfinyl and 2,3-dimethylbutanesulfinyl groups, of which the straight and branched chain alkanesulfinyl groups having from 1 to 4 carbon atoms are preferred; and PA1 lower alkylthio groups, which may have from 1 to 6, preferably from 1 to 4, carbon atoms in the alkyl part thereof, which may be straight or branched chain group such as those exemplified in relation to the alkyl group which may be included in substituents (a); examples of preferred such alkylthio groups include the methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio and 2,3-dimethylbutylthio groups, of which the straight and branched chain alkylthio groups having from 1 to 4 carbon atoms are preferred. PA1 (1) Compounds in which both R.sup.1 and R.sup.2 are independently selected from the group consisting of groups represented by --R.sup.5 (in which R.sup.5 is as defined above); PA1 (2) Compounds in which at least one of R.sup.1 and R.sup.2 represents an aryl group having at least one substituent selected from the group consisting of substituents (a), defined above; PA1 (3) Compounds in which R.sup.3 represents a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group; PA1 (4) Compounds in which R.sup.4 represents a substituted phenyl group having from 1 to 5 C.sub.1 -C.sub.6 alkoxy substituents; PA1 (5) Compounds in which X represents an oxygen atom; PA1 (6) Compounds in which A represents a 1,4-piperazin-1,4-diyl group. PA1 (7) R.sup.1 represents a substituted phenyl group having at least one C.sub.1 -C.sub.22 alkyl, C.sub.1 -C.sub.22 alkoxy or halogen substituent; PA1 (8) R.sup.1 represents a substituted phenyl group having at least one C.sub.1 -C.sub.6 alkyl C.sub.1 -C.sub.6 alkoxy or halogen substituent; PA1 (9) R.sup.2 represents an unsubstituted phenyl group or a substituted phenyl group having at least one substituent selected from the group consisting of C.sub.1 -C.sub.22 alkyl groups, C.sub.1 -C.sub.22 alkoxy groups, C.sub.1 -C.sub.6 haloalkyl groups and halogen atoms; PA1 (10) R.sup.2 represents a substituted phenyl group having at least one substituent selected from the group consisting of C.sub.1 -C.sub.22 alkyl groups, C.sub.1 -C.sub.22 alkoxy groups, C.sub.1 -C.sub.6 haloalkyl groups and halogen atoms; PA1 (11) R.sup.2 represents a substituted phenyl group having at least one substituent selected from the group consisting of C.sub.1 -C.sub.22 alkyl groups, C.sub.1 -C.sub.6 haloalkyl groups and halogen atoms; PA1 (12) R.sup.2 represents a substituted phenyl group having at least one substituent selected from the group consisting of C.sub.1 -C.sub.6 alkyl groups, C.sub.1 -C.sub.6 haloalkyl groups and halogen atoms; PA1 (13) R.sup.2 is as defined in any one of (10) to (12) above in which the substituent is at the meta position; PA1 (14) Compounds in which R.sup.3 represents a hydrogen atom; PA1 (15) Compounds in which R.sup.4 represents a substituted phenyl group having from 1 to 3 C.sub.1 -C.sub.6 alkoxy substituents, more especially from 1 to 3 C.sub.1 -C.sub.3 alkoxy substituents and most especially from 1 to 3 methoxy substituents; PA1 (16) Compounds in which B' represents a carbonyl group.
Also known are the N-nicotinoylpiperazine derivatives of Japanese Patent Application Kokai No. Sho. 60-193966, but these are only disclosed to have peripheral vasodilating and anti-hypertensive activities, and there is no suggestion that the compounds are PAF antagonists.
The compounds of the prior art referred to above all have structures different from those of the compounds of the present invention, although, in some cases, the prior compounds may share elements of the structures of the compounds of the present invention. In particular, none of the prior compounds is an N-acryloylpiperazine or N-acryloylhomopiperazine compound.
We have now discovered a series of new N-acryloylpiperazine and N-acryloylhomopiperazine derivatives which have excellent PAF antagonist activity and many of which have shown an excellent and wholly unexpected stability, even when administered orally, to give a high blood concentration. The activities of many of the compounds of the present invention have shown indications of being substantially better than those of the compounds of the prior art, including those referred to above and having structures similar to those of the compounds of the present invention.